Alexander Drilon, MD

Lori J. Wirth, MD

As reported inThe New England Journal of Medicine by Alexander Drilon, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues and by Lori J. Wirth, MD, of Massachusetts General Hospital, and colleagues, the phase I/II LIBRETTO-001 trial has shown marked activity of the RET kinase inhibitor selpercatinib in patient cohorts with RET fusion–positive non–small cell lung cancer (NSCLC) and RET-altered thyroid cancer.^1,2

The LIBRETTO-001 trial was performed at sites in 12 countries and enrolled adolescents and adults with any type of solid tumor harboring an activating RET alteration (ie, fusions or mutations) between May 2017 and June 2019.

The trial supported the May 2020 accelerated approval of selpercatinib in the following indications:

• Adults with metastatic RET fusion–positive NSCLC
• Adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant medullary thyroid cancer who require systemic therapy
• Adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion–positive thyroid cancer who require systemic therapy and who are radioactive iodine–refractory (if radioactive iodine is appropriate).

NSCLC Study

As reported by Drilon et al,¹ the trial enrolled 105 patients with RET fusion–positive advanced NSCLC who had previously received at least platinum-based chemotherapy and 39 previously untreated patients with advanced RET fusion–positive disease. Overall, 88% of previously treated patients received at least one dose of selpercatinib at the recommended phase II dose of 160 mg twice daily, with all previously untreated patients receiving 160 mg twice daily.

Previously treated patients had received a median of three systemic therapies, with 55% having received anti–PD-1 or anti–PD-L1 therapies and 48% having received multitargeted kinase inhibitors with anti-RET activity. The primary endpoint was objective response on independent review committee assessment.

Among the 105p reviously treated patients, an objective response was observed in 67 patients (64%). The median duration of response was 17.5 months, with 63% of responses ongoing at a median follow-up of 12.1 months. Responses were observed regardless of previous therapy with anti–PD-1 or anti–PD-L1 agents or multitargeted kinase inhibitors. Among 11 patients with measurable central nervous system metastases at baseline, an intracranial objective response was observed in 10 (91%), with a median duration of response of 10.1 months. Median progression-free survival was 16.5 months, with a 1-year rate of 67%.

Among the 39 previously untreated patients, an objective response was observed in 33 (85%). Median duration of response was not reached, with 90% of the responses ongoing at 6 months. Median progression-free survival was not reached, with a 1-year rate of 75%.

Among all patients, the most common grade ≥ 3 adverse events were hypertension (14%), increased alanine aminotransferase (ALT; 13%) levels, increased aspartate aminotransferase (AST; 10%) levels, hyponatremia (6%), and lymphopenia (6%). Adverse events led to death in six patients, with causes being sepsis in two patients and cardiac arrest, multiple organ dysfunction syndrome, pneumonia, and respiratory failure in one patient each; none of the deaths was considered related to treatment.

The investigators concluded: “Selpercatinib had durable efficacy, including intracranial activity, with mainly low-grade toxic effects in patients with RET fusion–positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated.”

Thyroid Cancer Study

As reported by Wirth et al,² the trial enrolled 55 patients with RET-mutant medullary thyroid cancer who had previously received vandetanib, cabozantinib, or both; 88 patients with RET-mutant medullary thyroid cancer who had not previously received vandetanib or cabozantinib; and 19 patients with previously treated RET fusion–positive thyroid cancer.

Overall, 82% of patients previously treated with vandetanib, cabozantinib, or both received selpercatinib at the recommended dose of 160 mg twice daily; 98% of those with RET-mutant medullary thyroid cancer not previously treated with vandetanib or cabozantinib and 95% of those with RET fusion–positive thyroid cancer received 160 mg twice daily. The primary endpoint was objective response on independent review committee assessment.

Among the 55 patients with previously treated RET-mutant medullary thyroid cancer, an objective response was observed in 38 (69%); median duration of response was not reached, with 86% of responses ongoing at 1 year; and median progression-free survival was not reached, with a 1-year rate of 82%. Among the 88 patients with RET-mutant medullary thyroid cancer who had not previously received vandetanib or cabozantinib, an objective response was observed in 64 (73%); median duration of response was 22.0 months, with 91% of responses ongoing at 1 year; and median progression-free survival was 23.6 months, with a 1-year rate of 92%. Among the 19 patients with previously treated RET fusion–positive thyroid cancer, an objective response was observed in 15 (79%); median duration of response was 18.4 months, with 71% of responses ongoing at 1 year; and median progression-free survival was 20.1 months, with a 1-year rate of 64%.

Among all patients, the most common adverse events of grade ≥ 3 were hypertension (21%), increased ALT levels (11%), increased AST levels (9%), hyponatremia (8%), and diarrhea (6%). Adverse events led to death in five patients, with causes being hemoptysis, postprocedure hemorrhage, sepsis, cardiac arrest, and cardiac failure in one patient each; none of the deaths was considered related to treatment.

The investigators concluded: “In this phase I/II trial, selpercatinib showed durable efficacy with mainly low-grade toxic effects in patients with medullary thyroid cancer with and without previous vandetanib or cabozantinib treatment.” 

DISCLOSURE: The study was funded by Loxo Oncology and others. Dr. Drilon has received honoraria from Foundation Medicine, Medscape, MORE Health, OncLive, Peerview, PeerVoice, Physicians Education Resources, Research to Practice, and Targeted Oncology; has served as a consultant or advisor to AbbVie, Archer Biosciences, AstraZeneca, Bayer, BeiGene, BerGenBio, Blueprint Medicines, Exelixis, Genentech/Roche, Helsinn Therapeutics, Hengrui Therapeutics, Ignyta, Lilly, Loxo, Monopteros, MORE Health, Pfizer, Remedica, Takeda/Ariad/Millennium, TP Therapeutics, Tyra Biosciences, Verastem, and 14ner/Elevation Oncology; has received research funding from Foundation Medicine; holds intellectual property in Wolters Kluwer; and has held other relationships with GlaxoSmithKline, Merck, Pfizer, PharmaMar, Puma Biotechnology, Taiho Pharmaceutical, and Teva. Dr. Wirth has served as a consultant or advisor to Ayala Pharmaceuticals, Bayer, Blueprint Medicines, CUE Biopharma, Eisai, Exelixis, Genentech, Lilly, Loxo, Merck, and Rakuten Medical.

REFERENCES

1. Drilon A, Oxnard GR, Tan DSW, et al: Efficacy of selpercatinib in RET fusion–positive non–small-cell lung cancer. N Engl J Med 383:813-824, 2020.

2. Wirth LJ, Sherman E, Robinson B, et al: Efficacy of selpercatinib in RET-altered thyroid cancers. N Engl J Med 383:825-835, 2020.